Despite considerable research effort and some success, cancer is still the second leading cause of death in the United States, claiming more than 500,000 lives each year according to American Cancer Society estimates. Traditional treatments are either invasive or expose the patient to considerable toxicity with often only modest success. Early detection, a result of better diagnostic practices and technology has improved the prognosis for many patients. Nevertheless, some cancers defy currently available treatment options, despite these improvements. Of the many forms of cancer that still pose a medical challenge, prostate, breast, lung, and liver claim the vast majority of lives each year.
Conventional treatments for many cancers, both in late and early stages, typically include surgery followed by radiation and/or chemotherapy both of which carry with them damaging side effects and considerable patient discomfort. Neither is completely effective against recurrence. For these reasons, it was desirable to provide improved and alternative techniques for treating cancer, particularly less invasive techniques that result in minimum or no collateral damage, and effective locally within target sites of the diseased organs. It was also desirable to provide techniques capable of being performed in a single or multiple treatment session(s), with minimal toxicity to the patient, and which could be targeted to the diseased tissues without requiring significant operator skill and input.
One such alternative technique is immunotherapy, which is a rapidly expanding type of therapy used for treating a variety of human diseases, including cancer. The FDA has approved a number of antibody-based cancer therapeutics. The emergence of antibody therapies is made possible by important advances in antibody technologies. The ability to engineer antibodies, fragments, and peptides with altered properties such as antigen binding affinity, molecular architecture, specificity, and valence has enhanced their use in therapies. The advantages of antibody engineering have overcome the limitations of mouse monoclonal antibodies. Cancer immunotherapeutics have made use of advances in the chimerization and humanization of mouse antibodies to reduce immunogenic responses in humans. High affinity human antibodies have also been obtained from transgenic mice that contain many human immunoglobulin genes. In addition, phage display technology, ribosome display, and DNA shuffling have allowed for the discovery of antibody fragments and peptides that have the desirable properties of high affinity and low immunogenicity for use as targeting ligands. All of these advances have made it possible to design an immunotherapy that has a desired antigen binding affinity, specificity, and minimal immune response.
The field of cancer immunotherapy makes use of markers that are expressed or over-expressed on cancer cells in comparison to normal cells. The identification of such markers is ongoing and the choice of a ligand/marker combination is critical to the success of any immunotherapy. Immunotherapy has fallen into several classes: (1) antibodies themselves that target growth receptors, disrupt cytokine pathways, or induce complement or antibody-dependent cytotoxicity; (2) direct arming of an antibody with a toxin, a radionucleotide, or a cytokine; (3) indirect arming of an antibody by attachment to immunoliposomes used to deliver a toxin or by attachment to an immunological cell effector (bispecific antibodies). Although armed antibodies have shown more potent tumor activity in clinical trials, there have been unacceptably high levels of toxicity. The disadvantage of therapies that rely on delivery of immunotoxins or radionucleotides (direct and indirect arming) has been that these agents are active at all times. There have been problems with damage to non-tumor cells and toxicity issues along with delivery challenges. Many immunotherapies have faced challenges with shed markers and delivery to the intended target. Cancer cells commonly shed antigen targets into the blood stream. Many antibody-based therapies are diluted by interaction with shed antigens. In addition, immune complexes can be formed between the immunotherapeutic and the shed antigen, which can lead to dose-limiting toxicities.
Generation of heat in a range of about 40° C. to about 46° C. (classical hyperthermia) can cause irreversible damage to diseased cells, whereas normal cells are not similarly affected. Diseased tissue may be treated by elevating the temperature of the individual cells contained within to a lethal level (cellular thermotherapy) using a suitable magnetic material confined to the vicinity of the cell and induction heating the material using an alternating magnetic field (AMF).
Hyperthermia may hold promise as a treatment for cancer because it induces instantaneous necrosis (typically called thermo-ablation) and/or a heat-shock response in cells (classical hyperthermia), leading to cell death via a series of biochemical changes within the cell. State-of-the-art systems that employ radio-frequency (RF) hyperthermia, such as annular phased array systems (APAS), attempt to tune E-field energy for regional heating of deep-seated tumors. Such techniques are limited by the heterogeneities of tissue electrical conductivities and that of highly perfused tissues, leading to the unsolved problems of ‘hot spot’ phenomena in unintended tissues with concomitant under-dosage in the desired areas. These factors make selective heating of specific regions with such E-field dominant systems very difficult.
Another strategy that utilizes RF hyperthermia requires surgical implantation of microwave- or RF-antennae or self-regulating thermal seeds. In addition to its invasiveness, this approach provides only limited (if any) treatment options for metastases because it requires knowledge of the precise location of the tumor, and is thus incapable of targeting undetected individual cancer cells or cell clusters not immediately adjacent to the primary tumor site. Clinical outcomes of these techniques are limited by problems with deposition of physical power to the desired tumor tissues.
Hyperthermia for cancer treatment using colloidal single domain magnetic suspensions (i.e., magnetic fluids) exposed to RF fields has been recognized for several decades. However, a major problem with magnetic fluid hyperthermia has been the inability to selectively deliver a lethal dose of particles to the tumor cells.